Scientists Link Parkinson's And Pesticides In Search For Cure

By Paul Kleyman

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Agrochemicals, organic gardening, identical twins, intravenous drug users, your cotton Levi's, rhubarb pie, a pot of coffee and a carton of cigarettes--all play a role in the increasingly complicated search for a cure for Parkinson's disease. The growing evidence that environmental factors, primarily the use of pesticides, are key to the development of Parkinson's was the subject of a featured symposium during the 40th Annual Meeting of the Society of Toxicology, held in San Francisco in March. The session was part of an international drive to coordinate genetic and environmental research on the illness.

The neurodegenerative condition--marked by uncontrolled tremor, rigidity and progressive postural instability--afflicts approximately 1.5 million people in the United States. It mainly strikes those age 50 or older.

ENVIRONMENTAL TRIGGER

"Based on accumulating evidence, we are increasingly confident that we can learn how to prevent this disease during the lifetime of our children," declared Kenneth Olden, director of the National Institute of Environmental Health Sciences (niehs), in Research Triangle Park, N.C., which sponsored the program. niehs is one of several of the National Institutes on Aging studying the disease. Calling Parkinson's "eminently preventable," Olden predicted, "I think it's going to turn out that there will be a genetic predisposition, so genes will play a very important role, but the environment will be what pulls the trigger."

Olden said that the panel was to be followed by a retreat for leading scientists on Parkinson's in May at the niehs headquarters. In addition, "Parkinson's Disease, Environment and Genes" is the theme for the 19th International Neurotoxicology Conference to be held in Colorado Springs, Colo., Aug. 25­28.

Only a decade ago scientists believed Parkinson's to be mainly inherited, said William Langston, a researcher at the Parkinson's Institute, a private research organization in Sunnyvale, Calif., but a surprising development in 1982 would eventually turn researchers' attention to external elements. That year, he recalled, intravenous drug users in Northern California began turning up in local health clinics with Parkinsonism. All were found to have used a bad batch of "China White," a synthetic narcotic. Working in a garage in Morgan Hill, a sleepy California suburb south of San Jose, a "clandestine chemist" erred in making a so-called designer drug, mppp. He "accidentally made an almost pure batch of mptp," said Langston, who is credited with the scientific detective work linking the drug to Parkinson's. Scientists found that in the body, mptp converts into MPP-plus, a chemical that "resembles paraquat," a widely used pesticide, he said.

Meanwhile, other evidence was mounting of nongenetic influences along the pathways to Parkinson's. In January 1999 a research team from the Parkinson's Institute released a study of an existing cohort of 15,934 pairs of white male twins, members of the generation that fought in World War II, who were born from 1917 to 1927. The investigators, led by Caroline Tanner, identified 193 individuals with confirmed cases of Parkinson's and compared monozygotic (identical) twins to dizygotic twins (conceived from separate fertilized eggs).

Tanner reasoned that if the disease were inherited researchers would find many more cases in which both identical twin brothers had developed Parkinson's than among pairs of fraternal twins. In fact, identical twins did contract Parkinson's more often--but only a very small number among those under age 50. Langston reported that Tanner's study and other research has established that only "a minuscule" number of Parkinson's cases are inherited, perhaps fewer than 5%. For those older than 50, Tanner found that among both identical and fraternal sets of twin, most of the individuals afflicted with Parkinson's did not share the disease with their brothers.

MANY SUBSTANCES

Webster Ross, also of the Parkinson's Institute, reported on several of the organization's studies. One headed by Lorene N. Nelson compared 496 patients found to have sporadic (nongenetic) cases of Parkinson's disease with 541 control subjects without the ailment. Patients were members of the Kaiser Permanente health plan. "What they found was that exposure to pesticides in the home and or garden was significantly associated with an increased risk of Parkinson's disease," he said. Patients who said they used pesticides in the home were about 70% more likely to develop the illness, those who used garden insecticides were 50% more likely to manifest the sickness, and those using herbicides were at 60% higher risk for contracting Parkinson's. He said that Tanner is now heading a study examining 84,000 licenced pesticide applicators in commercial agriculture in rural areas, along with their spouses. Ross stressed that when they identify the Parkinson's cases and the control group in this study cohort, the researchers plan to explore environmental influences besides pesticide use, such as natural compounds in the soil, and other lifestyle or health-risk factors, such as cigarette use or coffee consumption.

Ross reported that nearly 40 studies have found that "cigarette smoking has a protective effect against Parkinson's disease." In addition, he noted, coffee drinkers also seem to be guarded against Parkinson's. Findings from a longitudinal research group of 8,006 Japanese-American men living on the island of Oahu, Hawaii, showed that nondrinkers of coffee were five times more likely to develop Parkinson's that those who drank four to five cups of coffee a day. These stunning result are providing "very fruitful areas of research," he said.

"Parkinson's disease existed long before there was widespread use of pesticides," observed J. Timothy Greenamyre of the Emory University Department of Neurology, Atlanta. Equally important is the study of environmental exposures to natural compounds in food, air and water, he said, "even rhubarb," which contains a weak toxin that can damage dopamine cells. Parkinson's damages cullular brain structures, causing a decline in dopamine production.

Greenamyer studied the effects of the chemical rotenone on rats and found that it leads to a number of changes in the brain: loss of dopamine cells, formation of damaging structures called Lewy bodies, oxidative damage, and systemic impairment of essential structures called mitochondria. Rotenone, which occurs in nature, is applied to many home gardens and "on the Internet it's touted as the 'natural' or 'organic' alternative to synthetic pesticides," he said. More significant than his investigation of rotenone as such, he explained, is his goal to establish a single rodent model that scientists will be able to use to study the complex brain chemistry involved in environmentally induced damage to brain cells associated with Parkinson's.

TIP OF THE ICEBERG

Deborah A. Cory-Slechta, who chairs the Department of Environmental Medicine at the University of Rochester, Rochester, N.Y., showed a series of maps of the United States dramatically illustrating that the incidence of Parkinson's is most prevalent in the nation's primary agricultural areas, where agrochemicals are heavily used. In a study she began in 1999, she injected mice with paraquat, a weed killer that is sprayed aerially, and with maneb, a fungicide used in home gardens and "on millions of acres of potatoes, tomatoes, lettuce, corn, soybeans, cotton and fruit," Cory-Slechta said. She found that separately, the chemicals showed no lasting effect, but that in combination, the two reduced the levels of dopamine in the rodents' brains and caused the same type of nerve damage found in Parkinson's disease.

"What we're looking at may be the tip of the iceberg," she stated. "I don't think I was just lucky enough to have found the right combination." She stressed that the results call into question the current paradigm used to assess health risks of pesticides based on their individual effects, not in combination. "These current risk-assessment paradigms simply don't work, and we need to rethink them," she asserted. She also called for research to determine the levels to which humans are exposed to each pesticide. "Without that kind of data, it becomes very difficult to truly mimic human exposures in some of these models," she said.

Responding to a questioner who noted that paraquat and maneb are not used simultaneously in agriculture, Cory-Slechta explained, "What we are concerned about is when the compounds hit the human body, not when they're used in the field." For example, she said, with cotton, which is routinely sprayed with paraquat, parts of the plant not used to produce cloth become a supplement for cattle feed. As a result, Cory-Slechta noted, researchers need to find out whether the chemical enters the food chain. "When we have compounds that are food residues or are in water or any other source, we have to think about when they hit the human bloodstream or any other route of entry into the human body," she said.

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